GPC3 CAR T Cells With IL-15 and IL-21 for Recurrent ATRT and CNS Rhabdoid Tumors (RADIANT)

Официальное название

Robust Armored Dual-Cytokine (IL-15/IL-21) GPC3-CAR T Cells for Atypical Teratoid Rhabdoid Tumors and Central Nervous System Rhabdoid Tumors (RADIANT)

Обзор

This study is being conducted in patients with GPC3-positive brain tumors that have recurred or have not responded to standard therapy. Atypical teratoid rhabdoid tumors (ATRT) are aggressive tumors with poor outcomes and limited treatment options, particularly in young children. There is a need for new therapies that can improve outcomes while minimizing toxicity. This study evaluates a new experimental treatment using genetically engineered T cells (RADIANT-T cells) that target glypican-3 (GPC3), a protein expressed on tumor cells. These T cells are modified to express a chimeric antigen receptor (CAR) targeting GPC3, along with IL-15 and IL-21 to enhance their persistence and activity. The cells also include an inducible safety mechanism (iCasp9) that allows them to be eliminated if necessary. The purpose of this study is to determine the highest safe dose of RADIANT-T cells, evaluate their safety and side effects, assess how long they persist in the body, and determine whether they show anti-tumor activity in patients with GPC3-positive brain tumors.

Подробное описание

This is a Phase 1 dose-escalation study conducted at Texas Children's Hospital to evaluate RADIANT-T cells in patients with GPC3-positive brain tumors. Approximately 15-24 subjects will participate in the treatment portion of the study.

Autologous T cells are collected from the patient and genetically engineered using a retroviral vector to express a GPC3-specific chimeric antigen receptor along with IL-15 and IL-21. The modified T cells are expanded and tested for activity against GPC3-positive tumor cells prior to administration.

Patients receive a single dose of RADIANT-T cells administered intracavitarily during a planned surgical resection. Prior to administration, patients may receive premedication to reduce the risk of infusion reactions. During surgery, an Ommaya reservoir is placed to allow monitoring and management of potential treatment-related effects.

This is a dose-escalation study in which groups of patients receive increasing dose levels of RADIANT-T cells to determine the maximum tolerated dose. The dose administered to each patient depends on prior patient outcomes at lower dose levels.

Patients undergo clinical evaluations before treatment, including physical examination, laboratory testing, and imaging studies. After treatment, patients are monitored with physical exams, laboratory tests, cerebrospinal fluid assessments, and imaging to evaluate safety and tumor response.

Tumor assessments are performed by MRI at approximately 1 week and 4-6 weeks after treatment. Patients are followed longitudinally to assess safety, persistence of the modified T cells, and clinical outcomes. Long-term follow-up continues for up to 15 years after infusion, with more frequent visits early after treatment and less frequent visits over time.

Вмешательства

• Биопрепарат 21.15.GPC3-CAR T Cells
  Autologous T cells genetically engineered using retroviral vectors encoding a GPC3-specific CAR and IL-15 and IL-21 cytokines. The product also includes an inducible caspase-9 safety switch allowing pharmacologic elimination of the CAR T cells in the event of severe toxicity.

Первичные конечные точки

• Number of Participants with Dose-Limiting Toxicity [Срок оценки: 4 weeks after CAR T-cell administration]

Вторичные конечные точки (2)

• Maximum Tolerated Dose (MTD) of intratumoral and/or ICV injection of 21.15.GPC3-CAR T cells in treating patients with GPC3-positive recurrent or incompletely resected ATRT. [Срок оценки: 28 days]
• Response Rate [Срок оценки: 4-6 weeks after CAR T-cell administration]

Критерии участия

Procurement Inclusion Criteria:

• 1\) Diagnosis of GPC3-positive recurrent ATRT.
• 2\) Age ≥ 6 months
• 3\) Karnofsky/Lansky score ≥ 60%
• 4\) Informed consent explained to, understood by, and signed by patient/guardian; copy provided
• 5\) GPC3 expression by immunohistochemistry with extent score ≥ Grade 2 (>25% positive tumor cells) and intensity score ≥ 2 (scale 0-4)

Procurement Exclusion Criteria:

• 1\) No history of organ transplantation
• 2\) No known HIV positivity
• 3\) No active bacterial, fungal, or viral infection (except Hepatitis B or Hepatitis C virus infections)
• 4\) No other risk factors in which administration of the investigational agent is deemed not in the patient's best interest, in the opinion of the investigator

Treatment Inclusion Criteria:

• 1\) Age ≥ 6 months
• 2\) Diagnosis of treatment refractory or unresectable ATRT after standard of care therapy
• 3\) Lansky/Karnofsky score ≥ 60%
• 4\) Stable neurologic exam for 7 days prior to enrollment
• 5\) Stable or decreasing dose of steroids over past 7 days prior to surgery and administration of therapy (max allowable dose is 0.1mg/kg dexamethasone or equivalent per day)
• 6\) Not receiving any concurrent anti-cancer therapy.
• 7\) At least 6 weeks following craniospinal radiation therapy.
• 8\) At least 14 days wash-out needed following small volume radiotherapy (i.e., Stereotactic Radiosurgery (SRS)).
• 9\) At least 21 days or 5 half-lives (whichever is shorter) must have elapsed since any prior systemic therapy
• 10\) Received any other forms of immunotherapy ≤ 42 days before administration of investigational agent
• 11\) At least 28 days following bevacizumab
• 12\) Creatinine clearance as estimated by Cockcroft Gault or Schwartz ≥ 60 ml/min
• 13\) Total bilirubin < 3 times ULN for age
• 14\) INR ≤ 1.7
• 15\) Absolute neutrophil count > 500/μl
• 16\) Platelet count > 100,000/μl (can be transfused but must be achieved prior to enrollment)
• 17\) Hgb ≥ 7.0 g/dl (can be transfused)
• 18\) Pulse oximetry > 90% on room air
• 19\) Recovered from acute toxic effects of all prior chemotherapy and investigational agents before entering this study
• 20\) Sexually active patients must be willing to utilize one of the more effective birth control methods for 3 months after the T-cell infusion.
• 21\) Informed consent explained to, understood by and signed by patient/guardian. Patient/guardian given copy of informed consent

Treatment Exclusion Criteria:

• 1\) Pregnancy or lactation (for women at child-bearing age, birth control is required)
• 2\) Uncontrolled infection
• 3\) Known HIV positivity
• 4\) Active bacterial, fungal or viral infection (except Hepatitis B or Hepatitis C virus infections)
• 5\) History of organ transplantation

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 1 центр

• Texas Children's Hospital — Houston

Идентификаторы

NCT: NCT07513194 · H-58806, RADIANT

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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